PROJECT SUMMARY/ABSTRACT The Radiation Oncology and Cancer Imaging Program (ROCIP) has been created at the recommendation of the CCSG External Advisory Board and merges the previous Radiation Oncology Physics and Biology Program with Diagnostic Imaging. The ROCIP now has 74 members (56 primary, 18 associate) and is led by Drs. Albert Koong and David Piwnica-Worms with Dr. Junjie Chen as co-leader. Dr. Koong is a physician-scientist with expertise in hypoxia and the unfolded protein response who pioneered the use of stereotactic ablative radiotherapy for pancreatic cancer. Dr. Piwnica-Worms is a thought-leader in molecular imaging. Dr. Chen is an international authority in DNA repair. Radiation Oncology (RO) and Cancer Imaging (CI) constitute a multidisciplinary effort, emphasizing diagnosis, staging, treatment, and assessing response to multimodality therapy. The focus of CI is to develop novel imaging modalities to help optimize clinical decisions. The focus in RO is to develop advanced radiation therapy techniques that maximize the opportunity for cure while limiting treatment-related toxicity. The ROCIP is organized around four major themes: (1) DNA Repair; (2) Imaging Biomarkers of Response and Toxicity, (3) Immuno-Radiation Therapy; and (4) Imaging and Radiation Effectiveness. Each theme is addressed by a specific aim. Aim 1: To Identify tumor-specific vulnerabilities in DNA repair pathways that can be exploited for image-guided radiation therapy; Aim 2: To develop novel imaging techniques that predict response to radiotherapy and chemotherapy. Aim 3: To develop strategies in radiation sciences that potentiate the effects of immunotherapy and to visualize those effects in real time; and Aim 4: To develop advanced personalized imaging to enhance the effectiveness of photon and proton radiotherapy. The ROCIP's annual direct peer-reviewed funding totals $10.9M, of which $6.9M (63%) is from NCI. The program has published 1602 papers, of which 582 (36%) are intra-programmatic, 782 (49%) are inter-programmatic, and 978 (61%) have one or more external collaborators. Twenty-seven percent of articles were published in journals with IF >5 and 7% in journals with IF >10, including Nature, N Engl J Med, JAMA, Proc Natl Acad Sci USA, and Lancet Oncol. Program members have collectively used all 14 CCSG shared resources. Notable scientific accomplishments include identification of key pathways influencing DNA double-strand breakage and affecting PARP inhibition; discovery that fasting abrogates toxicity by enhancing DNA repair in intestinal crypt cells after chemoradiation; discovery of convergence between WNT signaling and DNA repair pathways in oncogenesis; identification of optimal combinations of radiotherapy and immunotherapy; novel proton therapy trials to define the role of proton therapy in various cancers; expansion of metabolic imaging with the introduction of clinical magnetic resonance hyperpolarization; and identification of radiation dose distributions to the heart and lungs that affect survival and normal tissue complications in patients with lung cancer. The breadth of these discoveries illustrates the importance of the Program's contributions to the scientific community.